A Critical Assessment of Combined Ligand-based and Structure-based Approaches to hERG Channel Blocker Modeling

摘要

Blockade of hERG channel prolongs the duration of the cardiac action potential and is a common reason for drug failure in preclinical safety trials. Therefore, it is of great importance to develop robust in silico tools to predict potential hERG blockers in the early stages of drug discovery and development. Herein we described comprehensive approaches to assess the discrimination of hERG-active and -inactive compounds by combining QSAR modeling, pharmacophore analysis, and molecular docking. Our consensus models demonstrated high predictive capacity and improved enrichment, and they could correctly classify 91.8% of 147 hERG blockers from 351 inactives. To further enhance our modeling effort, hERG homology models were constructed and molecular docking studies were conducted, resulting in high correlations (R²=0.81) between predicted and experimental binding affinities. We expect our unique models can be applied to efficient screening for hERG blockades, and our extensive understanding of the hERG-inhibitor interactions will facilitate the rational design of drugs devoid of hERG channel activity and hence with reduced cardiac toxicities.